The proposed studies would seek, as their major objective, to enhance present knowledge concerning a) the mechanisms of action of the antioxidanta butylated hydroxytoluene (BHT) and vitamin E, b) their effect on the hepatic peroxisome proliferation of liver tumors induced by peroxisome proliferators and c) the role of oxygen radical production in peroxisome proliferator induced liver tumors. The studies with BHT and vitamin E will test the hypothesis that persistent proliferation of peroxisomes leads to the neoplastic transformation of liver cells by increasing the intracellular production of DNA damagin H2O2 and other oxygen intermediates and that anti-oxidants by inhibiting lipid peroxidation would retard or inhibit this process. The majority of biological research on the anti-oxidant prevention of carcinogenesis has been done with genotoxic carcinogens such as polycyclic aromatic hydrocarbons. The proposed studies will employ altogether different or novel types of chemical carcinogens which exert unique biological and biochemical alterations in liver. These studies will include: 1) characterization of the affects of antioxidants BHT and vitamin E on hepatic peroxisome proliferation; 2) determination of the modulating effect of BHT and excess or deficiency of vitamin E on liver tumorigenesis by a hypolipidemic peroxisome proliferator, and 3) quantitation of oxygen radicals generated and their role in the accumulation of autofluorescent lipofuscin and DNA damage. If BHT and Vitamin E supplementation successfully prevent the liver carcinogenesis in rats, it is conceivable that they can be used in combination with hypolipidemic drugs for the treatment of patients which hyperlipidemia to minimize the unwarranted side effects.